Delving into the Latest Updates on BQ-123 with Synapse

Overview

Basic Info

Drug Type

Small molecule drug

Synonyms

+ [1]

Target

ETA

Mechanism

ETA antagonists(Endothelin receptor type A antagonists)

Therapeutic Areas

Nervous System Diseases

Active Indication

Brain Edema

Inactive Indication

Arrhythmias, CardiacBrain IschemiaDiabetic Ketoacidosis+ [6]

Originator Organization

Pharmazz, Inc.

Active Organization

Pharmazz, Inc.

Inactive Organization

University of Glasgow

Western Infirmary

Drug Highest PhasePhase 2

First Approval Date-

Regulation-

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Structure

Molecular FormulaC31H42N6O7

InChIKeyVYCMAAOURFJIHD-PJNXIOHISA-N

CAS Registry136553-81-6

Gene Sequence

Sequence Code 15188913

In people diagnosed with chronic kidney disease (CKD) anaemia is a common problem and is often treated with EPO (Erythropoietin). One form of EPO used is Darbepoetin (Aranesp®). EPO is safe to use but it has been associated with a rise in blood pressure (BP) in some individuals. The reasons for this are not clear. To try to explain this, this study will look at how EPO affects certain substances in the blood that influence how blood vessels contract and relax. This will be conducted by infusing small amounts of Acetylcholine, BQ123 and Noradrenaline into the arm vessels of volunteers using an established method called Forearm blood flow (plethysmography). Volunteers recruited for this study will include CKD patients undergoing therapy with Darbepoetin as part of their normal NHS care as well as healthy people not on treatment, who will act as controls. This is an observational pilot study of changes in physiology before and after Darbepoetin. It will provide valuable data for a later study comparing Darbepoetin to novel agents which work via different pathways to treat anaemia.

Start Date20 Feb 2017

Sponsor / Collaborator

Cambridge University Hospitals NHS Foundation Trust

[+1]

100 Clinical Results associated with BQ-123

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100 Translational Medicine associated with BQ-123

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100 Patents (Medical) associated with BQ-123

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1,706

Literatures (Medical) associated with BQ-123

31 Dec 2024·Blood Pressure

Endothelin-1- and acetylcholine-mediated effects in human and rat vessels: impact of perivascular adipose tissue, diabetes, angiotensin II, and chemerin

Article

Author: Danser, A. H. Jan ; Tan, Lunbo ; Cruz-López, Edwyn O. ; Verdonk, Koen ; Stolk, Daniël G. ; van den Bogaerdt, Antoon J.

OBJECTIVETo study the role of perivascular adipose tissue (PVAT) in the reactivity of rat and human vessels.METHODSIliac and mesenteric arteries were obtained from normotensive Sprague-Dawley rats, hypertensive transgenic (mRen2)27 rats overexpressing mouse renin, and (mRen2)27 rats made diabetic with streptozotocin. Human coronary arteries were obtained from donors. Concentration-response curves were constructed to endothelin-1 and acetylcholine with and without PVAT. The contribution of NO and endothelium-dependent hyperpolarization (EDH) were determined making use of the NO synthase inhibitor L-NAME and the EDH inhibitors apamin + TRAM-34. The endothelin type A and type B (ET_A, ET_B) receptor blockers BQ123 and BQ788, the chemerin inhibitors α-NETA and pravastatin, and the angiotensin receptor blocker losartan were also used.RESULTSIn rat iliac arteries, PVAT diminished endothelin-induced constriction, while the opposite was true in human coronaries. Coronary effects were unaltered by α-NETA, pravastatin, or losartan. ET_B receptor-mediated relaxation in iliac arteries occurred only with PVAT, and BQ123 blocked endothelin-1-induced constriction. Diabetes upregulated the anticontractile effects of PVAT. In rat mesenteric arteries, acetylcholine-induced relaxation with PVAT relied on NO, and on NO + EDH without PVAT. Diabetes upregulated the EDH component exclusively with PVAT.CONCLUSIONPVAT modulates ET-1-induced constriction in a vessel type-dependent manner. Its enhancing effects in coronaries involved neither chemerin nor angiotensin II. Its anticontractile effects in rat iliac arteries involved ET_B receptor-mediated relaxation. Diabetes upregulated PVAT's anticontractile effects. In mesenteric arteries, PVAT counterbalanced the EDH component of the relaxant effect of acetylcholine. Diabetes reversed this effect by upregulating the EDH component.

06 Nov 2024·Clinical Science

Complex regulation of tau phosphorylation by the endothelin system in brain microvascular endothelial cells (BMVECs): link to barrier function

Article

Author: Ergul, Adviye ; Jamil, Sarah ; Abdul, Yasir ; Albayram, Onder ; Karakaya, Eda ; Edwards, Jazlyn

AbstractEndothelin-1 (ET-1), the most potent vasoconstrictor identified to date, contributes to cerebrovascular dysfunction. ET-1 levels in postmortem brain specimens from individuals diagnosed with Alzheimer’s disease (AD) and related dementias (ADRD) were shown to be related to cerebral hypoxia and disease severity. ET-1-mediated vascular dysfunction and ensuing cognitive deficits have also been reported in experimental models of AD and ADRD. Moreover, studies also showed that ET-1 secreted from brain microvascular endothelial cells (BMVECs) can affect neurovascular unit integrity in an autocrine and paracrine manner. Vascular contributions to cognitive impairment and dementia (VCID) is a leading ADRD cause known to be free of neuronal tau pathology, a hallmark of AD. However, a recent study reported cytotoxic hyperphosphorylated tau (p-tau) accumulation, which fails to bind or stabilize microtubules in BMVECs in VCID. Thus, the study aimed to determine the impact of ET-1 on tau pathology, microtubule organization, and barrier function in BMVECs. Cells were stimulated with 1 μM ET-1 for 24 h in the presence/absence of ETA (BQ123; 20 μM) or ETB (BQ788; 20 μM) receptor antagonists. Cell lysates were assayed for an array of phosphorylation site-specific antibodies and microtubule organization/stabilization markers. ET-1 stimulation increased p-tau Thr231 but decreased p-tau Ser199, Ser262, Ser396, and Ser214 levels only in the presence of ETA or ETB antagonism. ET-1 also impaired barrier function in the presence of ETA antagonism. These novel findings suggest that (1) dysregulation of endothelial tau phosphorylation may contribute to cerebral microvascular dysfunction and (2) the ET system may be an early intervention target to prevent hyperphosphorylated tau-mediated disruption of BMVEC barrier function.

21 Aug 2024·Clinical Science

Endothelin-1 (ET-1) contributes to senescence and phenotypic changes in brain pericytes in diabetes-mimicking conditions

Article

Author: Ergul, Adviye ; Abdul, Yasir ; Jamil, Sarah ; Edgerton-Fulton, Mia

AbstractDiabetes mediates endothelial dysfunction and increases the risk of Alzheimer’s disease and related dementias. Diabetes also dysregulates the ET system. ET-1-mediated constriction of brain microvascular pericytes (BMVPCs) has been shown to contribute to brain hypoperfusion. Cellular senescence, a process that arrests the proliferation of harmful cells and instigates phenotypical changes and proinflammatory responses in endothelial cells that impact their survival and function. Thus, we hypothesized that ET-1 mediates BMVPC senescence and phenotypical changes in diabetes-like conditions. Human BMVPCs were incubated in diabetes-like conditions with or without ET-1 (1 µmol/L) for 3 and 7 days. Hydrogen peroxide (100 µmol/L H2O2) was used as a positive control for senescence and to mimic ischemic conditions. Cells were stained for senescence-associated β-galactosidase or processed for immunoblotting and quantitative real-time PCR analyses. In additional experiments, cells were stimulated with ET-1 in the presence or absence of ETA receptor antagonist BQ-123 (20 μmol/L) or ETB receptor antagonist BQ-788 (20 μmol/L). ET-1 stimulation increased β-galactosidase accumulation which was prevented by BQ-123. ET-1 also increased traditional senescence marker p16 protein and pericyte-specific senescence markers, TGFB1i1, PP1CA, and IGFBP7. Furthermore, ET-1 stimulated contractile protein α-SMA and microglial marker ostepontin in high glucose suggesting a shift toward an ensheathing or microglia-like phenotype. In conclusion, ET-1 triggers senescence, alters ETA and ETB receptors, and causes phenotypical changes in BMVPCs under diabetes-like conditions. These in vitro findings need to be further studied in vivo to establish the role of ETA receptors in the progression of pericyte senescence and phenotypical changes in VCID.

100 Deals associated with BQ-123

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External Link

KEGG	Wiki	ATC	Drug Bank
-	BQ-123	-	DB12054

R&D Status

10 top R&D records.

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Indication	Highest Phase	Country/Location	Organization	Date
Brain Edema	Phase 2	-	Pharmazz, Inc.	-
Pain	Preclinical	US	Pharmazz, Inc.	18 Oct 2017
Arrhythmias, Cardiac	Preclinical	GB	Western Infirmary	-
Brain Ischemia	Preclinical	US	-	-
Heart Failure	Preclinical	GB	University of Glasgow	-
Hypertension	Preclinical	JP	-	-
Hypertension, Pregnancy-Induced	Preclinical	US	-	-
Peripheral Vascular Diseases	Preclinical	JP	-	-
Ulcer	Preclinical	JP	-	-
Diabetic Ketoacidosis	Discovery	US	Pharmazz, Inc.	10 Sep 2016

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Clinical Result

Indication

Phase

Evaluation

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


ISC2023	Not Applicable	-	-	Intranasal BQ-123	cykcuevtfd(hjdgxgecei) = ydpwzzxufx rhvrmccspr (znirnykbte )	-	01 Feb 2023
NCT02124824 (CTgov)	Early Phase 1	Hydrops Fetalis \| Heart Failure	30	BQ-123 (Arm 1: Control)	oliowpexvr(xxrtjkkivj) = qzqfhcqqhb zfnnnixeos (clgblmykgs, ktjmsbzvdc - cyqdjqiipn) View more	-	20 Dec 2021
				BQ-123 (Arm 2: Heart Failure)	oliowpexvr(xxrtjkkivj) = hdwhxydyhp zfnnnixeos (clgblmykgs, roaqnmewov - etypteftdy) View more
NCT01395329 (NETS, CTgov)	Phase 4	Hypertension \| Prehypertension	42	FBF response to Sodium Nitroprusside+Nebivolol+ACh+BQ-788+BQ-123 (Nebivolol)	jqkqujhyqx(gubqwralsg) = ygkvshpqgk pbyahlgvfd (hfktugawqy, janrmwlerr - ombnfxroda) View more	-	06 Dec 2018
				FBF response to Sodium Nitroprusside+Metoprolol+ACh+BQ-788+BQ-123 (Metoprolol)	jqkqujhyqx(gubqwralsg) = ggcrvhkzqe pbyahlgvfd (hfktugawqy, umbtklvwch - ddycdixawm) View more
NCT00759408 (CTgov)	Phase 2	Hypertension, Pulmonary	38	BQ-123	ntqmlyqcev(aohdgpgodt) = fwrozclafp yvnroticie (tzunypwjul, aqbdhuhwuy - admvtkivfj) View more	-	24 Oct 2018
NCT00586820 (BQ-123, CTgov)	Phase 2	Myocardial Reperfusion Injury \| Microvascular Disease \| Non-St Elevated Myocardial Infarction	23	BQ-123 (BQ-123)	fvkbahquws(kbtatlbtse) = mlopjkfxrd yxjyvmzavz (lmjfxvbvht, kxnnehfczr - nymekoazea) View more	-	04 Jul 2014
				Placebo (Placebo)	fvkbahquws(kbtatlbtse) = axdwwmpibj yxjyvmzavz (lmjfxvbvht, zqcgtwvtvi - wbjzqwrzoe) View more